Nutritional support in advanced kidney disease: Role of oral and parenteral nutrition. T. Alp Ikizler, MD Vanderbilt University Medical Center

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1 Nutritional support in advanced kidney disease: Role of oral and parenteral nutrition T. Alp Ikizler, MD Vanderbilt University Medical Center

2 Goals To delineate the mechanisms through which wasting syndrome develops in advanced CKD To examine nutritional interventions that would counteract these catabolic signals by stimulating protein anabolism.

3 PEW is present in 12-18% of stages 3 and 4 CKD patients 2 studies reported PEW prevalence up to 18% in patients with early-stage CKD (3 and 4) 18% prevalence in CKD stages 3 and 4 patients in Brazil using SGA (n=122, age 55 ±11) 1 12% prevalence in CKD stage 4 patents in Australia, using SGA (n=56, age 70 ±14) 2 1. Sanches FM, et al. Am J Kidney Dis. 2008;52: Campbell KL, et al. Clin Nutr. 2008;27:

4 PEW is present in 30 to 65% or more of maintenance dialysis patients around the world Hemodialysis patients, USA, 47% (MIS) Hemodialysis patients, Sweden: 30 to 43% (SGA) Netherlands: 28% (SGA) Peritoneal dialysis patients, China 29 to 44% (SGA) 60% (MIS) Peritoneal dialysis patients, Brazil, 36 to 65% (SGA) Peritoneal dialysis patients, Korea, 40% (SGA) Adapted from TNT Renal

5 Etiology and Consequences of Protein Energy Wasting in CKD Loss of Kidney Function Uremic Toxins Co-Morbid Conditions (Diabetes, CVD, Depression) Dialysis-Associated Catabolism Infection Dietary Nutrient Intake Protein-Energy Wasting Sarcopenia CVD Inflammation Metabolic Derangements (Insulin Resistance, Metabolic Acidosis, IGF-1/GH Resistance) Frailty Carrero JJ et al on behalf of ISRNM; JREN 2013

6 Maintaining Protein Homeostasis in Humans: The Balancing Act Protein synthesis Protein Breakdown Growth Synthesis>Breakdown Wasting Breakdown>Synthesis Strategy in Disease States: Maximize appropriate protein synthesis Minimize inappropriate protein breakdown

7 Higher Negative Nitrogen Balance is Observed During Dialysis Days Borah et al KI 1978

8 Hemodialysis Induced Net Catabolism Biochemical structure of the membrane Increased protein catabolism with complement activating HD membranes Gutierrez & Bergstrom Kidney Int 1990 Pore size of the membrane Nutrient losses during hemodialysis? Higher losses with larger pore size Ikizler & Hakim Kidney Int 1994

9 Significant Amount of Amino Acids are Lost Into Dialysate during Dialysis total g/dialysis CU PMMA PS PD/Day Ikizler et al1994 Kidney Int

10 Plasma Amino Acid Concentrations Decrease During Hemodialysis Arterial Plasma Essential Amino Acids (mmol/l) Arterial Plasma Total Amino Acids (mmol/l) * * 15% * * 20% % % B D PD 0 B D PD Ikizler et al, AJP, 2002

11 Hemodialysis Causes Net Whole-body Protein Loss proteolysis synthesis net balance * * 10% 11% 96% 21% * * Pre-HD HD Post-HD Ikizler et al, AJP, 2002

12 Hemodialysis Causes Net Skeletal Muscle Protein Loss (mg/100ml/min) proteolysis synthesis net balance * * * * 27% 164% * * Pre-HD HD Post-HD Ikizler et al, AJP, 2002

13 Hypothesis: IDN compensates whole-body and muscle protein catabolism due to HD procedure resulting in net protein anabolism. IDN Amino Acids Dextrose Lipids Nutrient availability + Insulin (anabolic hormone) + Energy availability Compensation of whole-body and skeletal muscle catabolism Net protein anabolism

14 Plasma Amino Acids are Replenished During Intradialytic Nutritional Supplementation Total AA Nonessential AA Essential AA Branched-chain AA (mmol/l) mmol/l p<0.05 Control Pre HD During HD Post HD mmol/l p<0.05 IDPN Pre HD During HD Post HD Pupim et al, JCI, 2002

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16 Intradialytic Nutrition (Oral or Parenteral) Leads to Robust Whole-Body Protein Anabolism * P<0.05 versus Control, # P<0.05 versus PO

17 Oral supplements: Randomized Clinical Trials in HD/PD patients Slide Courtesy of Dr. Daniel Teta; Ikizler et al, Kidney Int, 2013

18 Oral nutrition supplementation provides benefits for HD or PD patients Hemodialysis and peritoneal patients using ONS experience: Increased calorie and protein intake Improved serum albumin, serum prealbumin levels Improved nutritional status (SGA) Increased body weight or BMI Increased lean body mass and bone density Improved physical function (grip strength) Improved quality of life and mental health scores Over the past 3 decades, 10 studies have shown outcome benefits of ONS therapy for CKD patients on dialysis Ikizler TA, et al. Kidney Int. 2013;84: TNT Renal Session 7 18

19 Meals During Dialysis Comparable Efficacy to Nutritional Supplements Veeneman et al, AJP, 2003

20 Meals During Dialysis Pros and Cons Counteracts HD related catabolism Improves nutritional status Increased protein synthesis Increased albumin Improves compliance Better PO4 and fluid removal Patient related risk Risk of aspiration Hypotension Patient and Unit Hygiene Infection control Inconvenience to staff

21 Meals During Dialysis Pros and Cons Practiced in France Germany Italy Spain Greece Japan China Turkey Sweden Thailand US VA Brazil NOT Practiced in United States (for profit) Canada????

22 Mortality After the Start of Dialysis Mortality rate (deaths per 100 patient years) * 1.44* * 1.62* * 1.42* 1.49* * 3.10* BE US SW IT ANZ CA FR UK GE JP 120 days days >365 days Excluded Spain due to under-reported morality in the first 30 days after initiation of dialysis *Adjusted hazard ratio for 120 vs days (p<0.05); Higher risk for >365 vs days (p<0.05) Cox model adjusted for age, sex, race, and diabetes as cause of ESRD, and stratified by study phase and accounted for facility clustering (N=86,886 patients in DOPPS census [ ])

23 Receipt of Oral Supplements During Dialysis is Associated with Improved Survival in MHD Patients Received Oral Supplements Did NOT Receive Oral Supplements

24 Receipt of Oral Supplements is Associated with Improved Hospitalization in MHD Patients N = 470 Received Oral Supplements Did NOT Receive Oral Supplements Cheu C et al. CJASN 2012

25 Intradialytic ONS is associated with improved survival in MHD patients with salb < 3.5 g/dl 29% reduction in the hazard of all-cause mortality (HR, 0.71; 95% CI, ) Weiner et al. Am J Kidney Dis 2014;63:276-85

26 Feeding During Dialysis: Is There a Down Side? Total of 8 studies examining the hemodynamic consequences 4 since 2001 (5 in 2 last decades) 3 US; 4 Europe; 1 Japan 3 used Acetate Dialysate Mostly excluded symptomatic CVD and Autonomic Dysfunction All used standard or similar meals 4 with decreased SBP or DBP; Diff: 2-4 mmhg 4 had no effect on BP 1 with worsened cramps 3 studies examined effects on Urea kinetics

27 Feeding During Dialysis: Why Not? The etiology of Uremic Protein Energy Wasting Syndrome is multifactorial (as in most chronic disease states) dietary intake + HD-associated catabolism + Inflammation + Insulin resistance -> wasting in CHD patients -> mortality and morbidity Nutritional Interventions -> convenient and safe; IDPN and Oral supplements can partially reverse the HD-induced catabolism (primarily by replenishing the amino acid pool). In-center meals are equally effective Need Revised Policies and Procedures to address issue Quantity; Ingredients; Packaging; Disposal Personalize to Patient

28 Start CKD-Specific Oral Nutritional Supplementation CKD 3-4: DPI target of > 0.8 g/kg/d (± AA/KA or ONS) CKD 5D: HD& PD: DPI target > 1.2 g/kg/d (ONS at home or during dialysis; in-center meals) Short-term Nutritional Therapy Goals: Salb > 3.8; SPrealb > 28; Weight or LBM gain Maintenance Nutritional Therapy Goals: Salb > 4.0 g/dl Sprealb > 30 mg/dl DPI > 1.2 (CKD-5D) & > 0.7 g/kg/d (CKD 3-4) DEI Kcal/kg/d Ikizler et al, on behalf of ISRNM Kidney Int, 2013

29 No Improvement or Deterioration Intensified Therapy Dialysis Rx alterations High-flux; Hemofiltration; FH; NH Increase quantity of oral therapy Tube feeding or PEG Parenteral interventions: IDPN (esp. if Salb <3.0 g/dl) TPN Ikizler et al, on behalf of ISRNM Kidney Int, 2013

30 Effects of IDPN on nutritional outcomes in MHD patients in randomized clinical trials Ikizler et al, on behalf of ISRNM Kidney Int, 2013

31 FineS design Malnourished MHD patients 182 patients Oral suppl during one year Oral suppl + IDPN during one year Follow-up: two years (treatment period + one year) Visits at day 0 and month 3, 6, 12, 18 and 24 FineS

32 Nutritional therapies Oral supplement: 5.4 kcal/kg/d 0.42 g protein/kg/d IDPN : 13.8 kcal/kg/hd (5.9 kcal/kg/d) 0.62 g AA/kg/HD (0.27 g AA/kg/d) Nitrogen supply: standard AA solution Energy supply: 50% standard fat emulsion 50% glucose FineS

33 Results: Nutritional status Serum albumin, g/l S NS Months Serum albumin, g/l Serum prealbumin, mg/l NS Months NS Months Control group IDPN group FineS

34 Patient cumulated survival Patient Survival NS Logrank p = Days Mean cumulative survival: 77% at 1 yr, 58% at 2 yr Death: Control: n = 36, IDPN: n = 40 FineS

35 Implications of Randomized Clinical Trials using Oral or Parenteral Supplementation in maintenance dialysis patients with PEW The route of administration of nutritional supplementation (i.e. oral or parenteral) does NOT have any significant effect on the response to therapy as long as equal and adequate amounts of protein and calories are provided. The optimal targets for dietary protein and energy intake in maintenance dialysis patients is >1.2 g/kg/day and >35 kcal/kg/day, respectively.

36 Towards the year 2020 Protein Energy Wasting in the Uremic State is complex Improving outcomes in maintenance dialysis requires a multi-faceted approach Nutritional (Renal specific) therapies should be considered in every MHD patient Consider as supplement not a replacement

37 Acknowledgements Jonathan Himmelfarb, MD Adriana Hung, MD, MPH Lara Pupim, MD Ayumi Shintani, PhD/MPH Raymond Hakim, MD, PhD Rebecca Wingard, RN, MSN Charles Ellis, PhD Paul Flakoll, PhD Naji Abumrad, MD Peter Stenvinkel, MD Eddie Siew, MD, MSCI Phyllis Egbert, MSN Mary Sundell, RD Brianna Laderbush, RD Cindy Booker, LPN Feng Sha Grace Jiang Andrew Vincz Funding NIH/NIDDK & NHLBI RCG/FMC SatelliteHealth grant program Vanderbilt Clinical and Translational Research Award NKF